Coatings

ABSTRACT

Lubricious coatings for medical devices and their uses are described.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/773,685, filed Jan. 27, 2020, which claims priority of U.S.Provisional Patent Application No. 62/797,853, filed Jan. 28, 2019, theentire contents of which are incorporated herein by reference.

FIELD

Described herein are coatings for medical devices and methods ofapplying those coatings.

BACKGROUND

Catheters and microcatheters are tubular devices that are used toconduct diagnostic and therapeutic endovascular interventions. Cathetersare often formed of thermoplastic polymers that have high frictionalforces. These high frictional forces make vascular navigation difficult.Providing a coated catheter or microcatheter with a lubricious coatingas described herein would be useful and beneficial.

SUMMARY

There herein described coatings can be applied to medical devices suchas medical devices that can be subjected to human tissues. In someembodiments, the coatings can be applied to medical devices can are usedinside vessels or other lumens. In some embodiments, the vessels can beblood vessels. In some embodiments, the medical devices can be cathetersor microcatheters.

The coatings can be synthetic and durable and lubricious. In someembodiments, the coatings can be ultra-violet (UV) cured. Lubriciouscoatings can reduce and/or minimize frictional forces between a medicaldevice, such as a catheter or microcatheter, and a vessel wall, therebyenhancing trackability of the medical device throughout the vasculature.The surfaces of catheters are modified with lubricious coatings toreduce the frictional forces and enhance the ability of the catheter tobe advanced through tortuous and distal vasculature.

In some embodiments, the herein described coating can include twolayers, a base coat and a top coat. The base coat functions as a tielayer between the catheter's thermoplastic polymer surface and the topcoat. The base coat is designed to adhere to the catheter and providebinding sites for the attachment of the top coat. The top coat isdesigned to adhere to the base coat and provide lubricity to reduce thefrictional forces when the catheter is moved in the vasculature.

The coatings can generally include: a base coat including a copolymer ofa first tetrahydrofurfuryl acrylate monomer and a second monomerincluding a functional group amenable to further derivatization andplurality of reactive moieties, and a top coat including a hydrophilicpolymer containing more than two reactive moieties per molecule.

The coatings can generally include: a base coat including a copolymer ofa first tetrahydrofurfuryl acrylate monomer and a second monomerincluding a functional group amenable to further derivatization andplurality of reactive moieties, and a top coat including a hydrophilicpolymer containing two or fewer (e.g., 2, 1, or 0, or less than two)reactive moieties per molecule.

Methods of coating a thermoplastic surface, such as a catheter ormicrocatheter surface, are also described. The methods can include:applying a base coat including a copolymer of a first tetrahydrofurfurylacrylate monomer and a second monomer to the thermoplastic surface, andapplying a top coat to the base coat, wherein the top coat includes ahydrophilic polymer.

DETAILED DESCRIPTION

Described herein are coatings for medical devices. In some embodiments,the coatings can increase the lubricity of the medical device. Thesemedical devices can include catheters and microcatheters that are formedat least partially of thermoplastic polymers/materials. Thethermoplastic polymers can include, but are not limited to,poly(olefins), poly(amides), poly(ethylene terephthalate),poly(urethanes), poly(ether sulfones), poly(carbonates), poly(vinylchloride), copolymers thereof, and derivatives thereof. In someembodiments, the thermoplastic polymers can include, but are not limitedto, poly(amides), poly(ethylene terephthalate), poly(urethanes),poly(ether sulfones), poly(carbonates), poly(vinyl chloride), copolymersthereof, and derivatives thereof.

These thermoplastic polymers can have high frictional forces. These highfrictional forces make vascular navigation difficult. Thus, the hereindescribed coatings can increase lubricity of the thermoplastic polymersurfaces. In some embodiments, the coatings can include a base coat anda top coat. The base coat functions as a tie layer between thecatheter's thermoplastic polymer and the top coat. The base coat isdesigned to adhere to the catheter and provide binding sites for theattachment of the top coat. The top coat is designed to adhere to thebase coat and provide lubricity to reduce the frictional forces when thecatheter is moved in the vasculature.

In some embodiments, the base coat includes a polymer that is acopolymer of a first tetrahydrofurfuryl acrylate monomer and at leastone other monomer with functional groups capable of further chemicalreaction such as hydroxyl, amine, and carboxylic acid groups. In someembodiments, the at least one other monomer including hydroxyl groupscan be hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropylacrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate,hydroxybutyl methacrylate, combinations thereof, and derivativesthereof. In some embodiments, the at least one other monomer includingamine groups can be N-(3-aminopropyl) methacrylamide, 2-aminoethylmethacrylate, 2-aminoethyl methacrylamide, combinations thereof, andderivatives thereof. In some embodiments, the at least one other monomerincluding carboxylic acids can be acrylic acid, methacrylic acid,beta-carboxyethyl acrylate, combinations thereof, and derivativesthereof.

To prepare the base coat copolymer, the two or more monomers andoptionally an initiator can be dissolved in a solvent. The solvent canbe any solvent that dissolves the two or more monomers and the optionalinitiator. Solvents can include benzene, toluene, xylene,dimethylformamide, dimethyl sulfoxide, dioxane, 2-methyltetrahydrofuran,anisole, benzonitrile, chlorinated aromatic solvents, diisopropyl ether,diglyme, butanol, and combinations thereof.

Initiators can be used to start the polymerization of the monomers inthe solution. The polymerization can be initiated byreduction-oxidation, radiation, heat, or any other method known in theart. Radiation cross-linking of the monomers in solution can be achievedwith ultraviolet light or visible light with suitable initiators orionizing radiation (e.g. electron beam or gamma ray) without initiators.Polymerization can be achieved by application of heat, either byconventionally heating the solution using a heat source such as aheating well, or by application of infrared light to the monomers insolution.

In some embodiments, the initiator is azobisisobutyronitrile (AIBN) or awater soluble AIBN derivatives (2,2′-azobis(2-methylpropionamidine)dihydrochloride), or 4,4′-azobis(4-cyanopentanoic acid). Otherinitiators can include N,N,N′,N′-tetramethylethylenediamine, ammoniumpersulfate, benzoyl peroxides, and combinations thereof, includingazobisisobutyronitriles.

In some embodiments, the initiator concentration can be from about 0.25%w/w to about 2% w/w of the mass of the monomers in solution.

In some embodiments, the polymerization reaction can be performed atelevated temperatures, such as in the range from about 65° C. to about85° C.

After the polymerization is completed, the copolymer can be recovered byprecipitation in a non-solvent and dried under vacuum.

The resulting copolymer can have a molecular weight between about 15,000g/mole and about 150,000 g/mole or between 25,000 g/mole to 100,000g/mole. This molecular weight can be derived by gel permeationchromatography with poly(styrene) or poly(methyl methacrylate) molecularweight standards.

Following polymerization, reactive groups, such as acrylates and/ormethacrylates, are added to the copolymer via the hydroxyl, amine,and/or carboxylic acid groups of the second or more monomers. Ingeneral, the derivatization compound is a hetero-bifunctional compound.One moiety reacts with the hydroxyl, amine, and/or carboxylic acidgroups of the copolymer. The other moiety is an acrylate or methacrylategroup. Suitable derivatization compounds include 2-isocyanatoethylacrylate, 2-isocyanatoethyl methacrylate, acrylic acidN-hydroxysuccinimide ester, methacrylic acid N-hydroxysuccinimide ester,hetero-bifunctional poly(ethylene glycol) with acrylate and isocyanategroups, combinations thereof, and derivatives thereof.

To prepare the derivatized copolymer, the copolymer, and derivatizationcompound, and optionally any catalyst, can be dissolved in a solvent. Ingeneral, any solvent that dissolves the components can be used. Solventscan include dimethyl formamide, dimethyl sulfoxide, toluene, acetone,acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, andcombinations thereof.

When reacting a derivatization with a nucleophilic group of the basecoat copolymer, the molar equivalent of derivatization agent can rangefrom about 5% to about 80% or about 10% to about 50% of the availablenucleophilic groups. This level of derivatization corresponds to a rangeof 4 to 50 reactive groups per molecule. Further, in some embodiments, aLewis base can be added of as a catalyst. Lewis bases can includetriethylamine and pyridine. The Lewis base can be provided at aconcentration of about 1% to about 10% of the moles of thederivatization compound added.

The reaction can proceed at elevated temperatures, such as about 45° C.to form the base coat. After the derivatization is complete, thecompleted, decorated copolymer can be recovered by precipitation in anon-solvent and dried under vacuum. In some embodiments, the reactioncan proceed at ambient temperatures (e.g., 15-25, e.g., 20° C.).

The top coat can be formed atop the base coat. The top coat polymer caninclude a core, hydrophilic polymer that is derivatized withpolymerizable groups. The core hydrophilic polymer can be anynaturally-occurring or synthetic polymer, derivatives thereof andcombinations thereof. In some embodiments, the core hydrophilic polymeris at least to some degree, soluble in water.

The structure of the core hydrophilic polymer can be linear or branched,including graft, star, comb, brush, and dendrimer structures.

In some embodiments, the core hydrophilic polymer includes Formula (I),which includes two or more hydroxyl moieties, which may serve as pointsof attachment for additional moieties, including, for example,ethylenically unsaturated groups including acrylates, methacrylates,acrylamides, methacrylamides, combinations thereof, and derivativesthereof. In some embodiments, the core hydrophilic polymer includesFormula (I), which includes four hydroxyl moieties, which may serve aspoints of attachment for the additional moieties. In some embodiments,the core hydrophilic polymer includes Formula (I), which includes eighthydroxyl moieties, which may serve as points of attachment for theadditional moieties. In some embodiments, each of the hydroxyls of thecore hydrophilic polymer may be functionalized with an ethylenicallyunsaturated moiety. In some embodiments, the resulting molecule (FormulaII), when there is a plurality of such molecules, includes an average ofless than two ethylenically unsaturated moieties per molecule. In someembodiments, the plurality of molecules includes an average of about 1.2to 1.6 reactive moieties per molecule. In some embodiments, theplurality of molecules includes two or fewer ethylenically unsaturatedmoieties per molecule and an average of about 1.0 to 1.9 moieties permolecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 0.01 to less than 2moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 0.1 to less than 2moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 0.3 to less than 2moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 0.6 to less than 2moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 0.9 to less than 2moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 1 to less than 2moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 0.1 to about 1moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 1.0 to about 1.8moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 1.2 to about 1.8moieties per molecule in the plurality.

In some embodiments, each molecule in the plurality of moleculesincludes two or fewer ethylenically unsaturated moieties and theplurality of molecules includes an average of about 1.2 to about 1.6moieties per molecule in the plurality.

Thus, in some embodiments, the resulting molecule includes a branchedhydrophilic polymer with two or more arms, wherein each arm is a linearpolymer and having 0, 1, or 2 ethylenically unsaturated moieties suchthat the molecule includes less than an average of two ethylenicallyunsaturated moieties and an average of about 1.2 to 1.6 (e.g., about0.1-1.9, e.g. about 0.5-1.8, e.g., about 1.0-1.7, e.g., about 1.5-1.7)ethylenically unsaturated moieties per molecule when there is aplurality of such molecules.

Thus, in some embodiments, Formula I has a structure Z—(OH)_(n), where nis two or more, and Z is a C₅₋₁₈H₈₋₃₀O₀₋₅ moiety. In some embodiments, nis 2-8. In some embodiments, n is 4-8. In some embodiments, n is 4. Insome embodiments, n is 8. In some embodiments, Z is a C₁₅₋₁₈H₂₄₋₃₀O₂₋₅moiety. In some embodiments, Z is a C₅₋₆H₈₋₁₀O₀₋₁ moiety. In someembodiments, Z is a C₁₈H₃₀O₅ moiety and n is 8. In some embodiments, Zis a C₁₅H₂₄O₂ moiety and n is 8. In some embodiments, Z is a C₆H₁₀Omoiety and n is 4. In some embodiments, Z is a C₅H₈ moiety and n is 4.

In some embodiments, Formula I is a hexaglycerol, tripentaerythritol,3,3′-oxybis(propane-1,2-diol), or 2,2-bis(hydroxymethyl)propane-1,3-diolmoiety.

In some embodiments, Formula I is a moiety selected from:

In some embodiments, Formula II has a structure(Z—((OCH₂CH₂OH)_(n-j))—((OCH₂CH₂X)_(j)), wherein Z is defined as inFormula I, j is greater than 0 to less than 2, and X is an ethynicallyunsaturated group. In some embodiments, j is about 0.01 to less than 2.In some embodiments, j is about 0.1 to less than 2. In some embodiments,j is about 0.3 to less than 2. In some embodiments, j is about 0.6 toless than 2. In some embodiments, j is about 0.9 to less than 2. In someembodiments, j is about 1.0 to less than 2. In some embodiments, j isabout 0.01 to about 1.0. In some embodiments, j is about 0.1 to about1.0. In some embodiments, j is about 1.2 to about 1.8. In someembodiments, j is about 1.2 to about 1.6. In some embodiments, j isabout 1.4 to about 1.5. In some embodiments, the ethynically unsaturatedgroup is independently selected from acrylates, methacrylates,acrylamides, methacrylamides, combinations thereof, or derivativesthereof. In some embodiments, the ethynically unsaturated group isindependently selected from an acrylate, a methacrylate, an acrylamide,or a methacrylamide.

Polymer used for the top coat can include, but are not limited tonaturally-occurring polymers such as proteins, collagen, albumin,fibrin, elastin, polypeptides, oligonucleotides, polysaccharides,hyaluronic acid, gelatin, chitosan, alginate, cellulose, carboxymethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, anddextran.

Polymer used for the top coat can include, but are not limited tosynthetic polymers such as poly(ethers), poly(ethylene glycol),poly(ethylene oxide), poly(propylene glycol), poly(lactams),poly(vinylpyrrolidone), poly(acrylates), poly(urethanes),poly(anhydrides), poly(amino acids), poly(carboxylic acids),poly(amides), poly(vinyl alcohol), and poly(phosphazenes).

Molecular weights of the hydrophilic polymers can range from about 500amu to about 100,000 amu or from about 1,000 amu to about 40,000 amu.

Reactive groups, such as, but not limited to acrylates and/ormethacrylates, can be added to the polymer via any convenient reactivemoiety, such as hydroxyls, amines, or carboxylic acids, with aderivatization compound. In some embodiments, the derivatizationcompound can be a hetero-bifunctional compound. One moiety can reactwith the hydroxyl, amine, and/or carboxylic acid groups of thecopolymer. The other moiety can be an acrylate or methacrylate group.

In some embodiments, the derivatization compound can include acryloylchloride, methacryloyl chloride, 2-isocyanatoethyl acrylate,2-isocyanatoethyl methacrylate, acrylic acid N-hydroxysuccinimide ester,methacrylic acid N-hydroxysuccinimide ester, hetero-bifunctionalpoly(ethylene glycol) with acrylate and isocyanate groups, combinationsthereof, and derivatives thereof.

To prepare the derivatized polymer, the polymer, derivatizationcompound, and the optional catalyst are dissolved in a solvent. Ingeneral, any solvent that dissolves the top coat polymer, derivatizationagent, and the optional catalyst can be used. Solvents can includearomatic and chlorinated solvents, including benzene, toluene, xylene,dichloromethane, chloroform, and combinations thereof.

When reacting a derivatization agent with a reactive moiety of the topcoat polymer, the target derivatization corresponds to less than twogroups per molecule. Additionally, in some embodiments, thederivatization can include addition of a Lewis base as a catalyst. Insome embodiments, the Lewis base can be triethylamine and pyridine, in aconcentration of about 1% to about 10% of the moles of thederivatization compound added.

In some embodiments, the derivatization reaction proceeds at roomtemperature.

After the derivatization is complete, an activated polymer can berecovered by precipitation in a non-solvent and dried under vacuum.

The base coat can be applied to a medical device surface, e.g., athermoplastic material. The catheter is first cleaned by a solvent wipeto remove any gross contamination from its surface. In some embodiments,the catheter is wiped with a solvent. In some embodiments, any solventcan be used if it does not dissolve or degrade the thermoplasticmaterial of the catheter. Solvents can include glycol ethers, methylethyl ketone, chlorinated solvents, tetrahydrofuran, hexane, ethylacetate and acetone.

Following solvent cleaning, in some embodiments, the catheter shaft canbe plasma treated to further clean its surface. In some embodiments, thecatheter is not plasma treated. Plasmas derived from various gases canbe used. In some embodiments, the plasma gases can be argon and oxygen.In some embodiments, both argon and oxygen plasmas can be used.

The base coat solution can include the solvent, base coat copolymer, anoptional initiator, and an optional surfactant. Generally, any solventor mixtures of solvents may be utilized, provided that the componentscan be dissolved into the solvent or solvent mixtures. Solvents caninclude water, alcohols, glycol ethers, aromatics, polar aproticsolvents, and combinations thereof. In some embodiments, the solvent caninclude methanol, ethanol, isopropyl alcohol, 2-ethoxy ethanol,propylene glycol monomethyl ether acetate, benzene, toluene, xylene,dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

The base coat copolymer can be dissolved into the solvent at aconcentration ranging from about 0.2% w/w to about 35% w/w, about 0.2%w/w to about 40% w/w, about 0.2% w/w to about 50% w/w, about 0.5% w/w toabout 35% w/w, about 0.5% w/w to about 40% w/w, about 0.5% w/w to about50% w/w, about 1% w/w to about 35% w/w, about 1% w/w to about 40% w/w,or about 1% w/w to about 50% w/w, depending on the desired viscosity ofthe basecoat solution. In some embodiments, the base coat copolymerconcentration is about 15% w/w.

In some embodiments, if included, initiators can include Norrish Type Iinitiators, Norrish Type II initiators, and combinations thereof.Norrish Type I or free-radical photo-initiators can include benzoinderivatives, methylolbenzoin and 4-benzoyl-1,3-dioxolane derivatives,benzilketals, α,α-dialkoxyacetophenones, α-hydroxy alkylphenones,α-aminoalkylphenones, acylphosphine oxides, bisacylphosphine oxides,acylphosphine sulphides, halogenated acetophenone derivatives, or acombination thereof. In some embodiments, Norrish Type I photoinitiatorscan include Irgacure 2959 (2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone), Irgacure 651 (benzildimethyl ketal or2,2-dimethoxy-1,2-diphenylethanone, Ciba-Geigy), Irgacure 184(1-hydroxy-cyclohexyl-phenyl ketone as the active component,Ciba-Geigy), Darocur 1173 (2-hydroxy-2-methyl-1-phenylpropan-1-one asthe active component, Ciba-Geigy), Irgacure 907(2-methyl-1-[4-(methylthio)phenyl]-2-morpholino propan-1-one,Ciba-Geigy), Irgacure 369(2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-one as theactive component, Ciba-Geigy), Esacure KIP 150 (poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}, FratelliLamberti), Esacure KIP 100 F (blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one} and2-hydroxy-2-methyl-1-phenyl-propan-1-one, Fratelli Lamberti), EsacureKTO 46 (blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one},2,4,6-trimethylbenzoyldiphenyl-phosphine oxide and methylbenzophenonederivatives, Fratelli Lamberti), acylphosphine oxides such as LucirinTPO (2,4,6-trimethylbenzoyl diphenyl phosphine oxide, BASF), Irgacure819 (bis(2,4,6-trimethylbenzoyl)-phenyl-phosphine-oxide, Ciba-Geigy),Irgacure 1700 (25:75% blend ofbis(2,6-dimethoxybenzoyl)2,4,4-trimethyl-pentyl phosphine oxide and2-hydroxy-2-methyl-1-phenyl-propan-1-one, Ciba-Geigy), or a combinationthereof.

In some embodiments, mixtures of type I photo-initiators can be used.

Norrish Type II photo-initiators can also be used in the base coatformulation. These initiators can include aromatic ketones such asbenzophenone, xanthone, derivatives of benzophenone (e.g.chlorobenzophenone), blends of benzophenone and benzophenone derivatives(e.g. Photocure 81, a 50/50 blend of 4-methyl-benzophenone andbenzophenone), Michler's Ketone, Ethyl Michler's Ketone, thioxanthoneand other xanthone derivatives like Quantacure ITX (isopropylthioxanthone), benzil, anthraquinones (e.g. 2-ethyl anthraquinone),coumarin, or chemical derivatives or combinations of thesephotoinitiators.

In some embodiments, the base coat formulation can include combinationsof Norrish Type I and Norrish Type II initiators.

The initiator concentration in the solvent can range from about 0.1% toabout 6% w/w. In some embodiments, initiator concentration in thesolvent can be about 0.6% w/w.

The base coat solution may also optionally include a surfactant. In someembodiments, any surfactant may be used. Surfactants can include sodiumlauryl sulfate, Tween 20, Span 80, Triton X-100, Pluronic F68, PluronicL-81, combinations thereof, and derivatives thereof. The optionalsurfactant can be dissolved into the selected solvent at a concentrationranging from about 0.1% w/w to about 15% w/w. In some embodiments, thesurfactant concentration is about 0.8% w/w.

In some embodiments, to apply the base coat to a catheter, the length ofthe catheter desired to be coated is inserted into the base coatsolution. The dip time, or amount of time the catheter spends in thebase coat solution, ranges from about 0.2 to about 10 minutes, about 0.5to about 10 minutes, about 2 to about 8 minutes, about 3 to about 6minutes, or about 0.5 to about 8 minutes. In some embodiments, the diptime can be about 5 minutes.

In some embodiments, to apply the base coat to a catheter, the length ofthe catheter desired to be coated is inserted into the base coatsolution. The dip time, or amount of time the catheter spends in thebase coat solution, ranges from about 0.2 seconds to about 10 minutes,about 1 second to about 10 minutes, about 2 seconds to about 8 minutes,about 3 seconds to about 6 minutes, or about 0.5 seconds to about 8minutes.

In some embodiments, to apply the base coat to a catheter, the length ofthe catheter desired to be coated is inserted into the base coatsolution. The dip time, or amount of time the catheter spends in thebase coat solution, ranges from about 0.2 seconds to about 10 seconds,about 1 second to about 10 seconds, about 2 seconds to about 8 seconds,about 3 seconds to about 6 seconds, or about 0.5 seconds to about 8seconds. In some embodiments, the dip time can be about 5 seconds.

In other embodiments, the base coat can be applied by spraying,brushing, spin coating, or the like, or a combination thereof includingor not including dip coating.

In some embodiments, only portions of the catheter are coated. Thereinportions of the catheter can be masked so that base coat is not appliedto the masked regions.

After dip coating or otherwise applying the base coat, the catheter isexposed to ultraviolet radiation with a wavelength ranging from about 10nm to about 400 nm, about 100 nm to about 400 nm, about 200 nm to about400 nm, about 200 nm to about 300 nm, or about 300 nm to about 400 nm.Combinations of wavelengths in this range can also provide a suitablebase coat. In one embodiment, ultraviolet radiation can be applied by afirst wavelength between about 200 nm to about 300 nm and a secondwavelength between about 300 nm to about 400 nm. In one embodiment,wavelengths can include 254 and 365 nm.

The cure time, or amount of time the catheter is exposed to ultravioletradiation, ranges from about 0.5 to about 10 minutes, about 1 to about10 minutes, about 1 to about 8 minutes, about 0.5 to about 6 minutes,about 1 to about 6 minutes, about 1 to about 3 minutes, or about 0.5 toabout 30 minutes. In one embodiment, the cure time is about 2 minutes.

The cure time, or amount of time the catheter is exposed to ultravioletradiation, ranges from about 0.5 seconds to about 10 minutes, about 1second to about 10 minutes, about 1 second to about 8 minutes, about 0.5seconds to about 6 minutes, about 1 second to about 6 minutes, about 1second to about 3 minutes, or about 0.5 seconds to about 30 minutes.

The cure time, or amount of time the catheter is exposed to ultravioletradiation, ranges from about 0.5 seconds to about 10 seconds, about 1second to about 10 seconds, about 1 second to about 8 seconds, about 0.5seconds to about 6 seconds, about 1 second to about 6 seconds, about 1second to about 3 seconds, or about 0.5 seconds to about 30 seconds. Inone embodiment, the cure time is about 30 seconds.

In some embodiments, the base coat application process is complete afterthe completion of the cure time.

The top coat can be applied to a completed base coat. The top coatsolution can include the solvent, a top coat polymer, an optionalinitiator, and an optional surfactant. In general, any solvent ormixtures of solvents may be utilized, provided that the components canbe dissolved into the solvent or solvent mixtures. Suitable solvents caninclude water, alcohols, glycol ethers, aromatics, polar aproticsolvents, and combinations thereof. In some embodiments, the solvent caninclude methanol, ethanol, isopropyl alcohol, 2-ethoxy ethanol,propylene glycol monomethyl ether acetate, benzene, toluene, xylene,dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

The top coat polymer can be dissolved into the selected solvent at aconcentration ranging from about 5% w/w to about 75% w/w, about 5% w/wto about 80% w/w, about 5% w/w to about 90% w/w, about 10% w/w to about80% w/w, about 10% w/w to about 75% w/w, about 5% w/w to about 50% w/w,about 5% w/w to about 40% w/w, about 5% w/w to about 40% w/w, about 20%w/w to about 40% w/w, about 20% w/w to about 30% w/w, depending on thedesired viscosity of the top coat solution. In one embodiment, the topcoat polymer concentration is about 25% w/w.

The optional initiator can include Norrish Type I initiators, NorrishType II initiators, and combinations thereof. Norrish Type I orfree-radical photo-initiators can inlcude benzoin derivatives,methylolbenzoin and 4-benzoyl-1,3-dioxolane derivatives, benzilketals,α,α-dialkoxyacetophenones, α-hydroxy alkylphenones,α-aminoalkylphenones, acylphosphine oxides, bisacylphosphine oxides,acylphosphine sulphides, halogenated acetophenone derivatives, and thelike. Norrish Type I photoinitiators can include Irgacure 2959(2-hydroxy-4′-(2-hydroxyethoxy)-2-methyl propiophenone), Irgacure 651(benzildimethyl ketal or 2,2-dimethoxy-1,2-diphenylethanone,Ciba-Geigy), Irgacure 184 (1-hydroxy-cyclohexyl-phenyl ketone as theactive component, Ciba-Geigy), Darocur 1173(2-hydroxy-2-methyl-1-phenylpropan-1-one as the active component,Ciba-Geigy), Irgacure 907(2-methyl-1-[4-(methylthio)phenyl]-2-morpholino propan-1-one,Ciba-Geigy), Irgacure 369(2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-one as theactive component, Ciba-Geigy), Esacure KIP 150 (poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}, FratelliLamberti), Esacure KIP 100 F (blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one} and2-hydroxy-2-methyl-1-phenyl-propan-1-one, Fratelli Lamberti), EsacureKTO 46 (blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one},2,4,6-trimethylbenzoyldiphenyl-phosphine oxide and methylbenzophenonederivatives, Fratelli Lamberti), acylphosphine oxides such as LucirinTPO (2,4,6-trimethylbenzoyl diphenyl phosphine oxide, BASF), Irgacure819 (bis(2,4,6-trimethylbenzoyl)-phenyl-phosphine-oxide, Ciba-Geigy),Irgacure 1700 (25:75% blend ofbis(2,6-dimethoxybenzoyl)2,4,4-trimethyl-pentyl phosphine oxide and2-hydroxy-2-methyl-1-phenyl-propan-1-one, Ciba-Geigy), and the like.Also, mixtures of type I photo-initiators can be used.

Norrish Type II photo-initiators that can be used include aromaticketones such as benzophenone, xanthone, derivatives of benzophenone(e.g. chlorobenzophenone), blends of benzophenone and benzophenonederivatives (e.g. Photocure 81, a 50/50 blend of 4-methyl-benzophenoneand benzophenone), Michler's Ketone, Ethyl Michler's Ketone,thioxanthone and other xanthone derivatives like Quantacure ITX(isopropyl thioxanthone), benzil, anthraquinones (e.g. 2-ethylanthraquinone), coumarin, or chemical derivatives or combinationsthereof.

In some embodiments, the top coat formulation can include combinationsof Norrish Type I and Norrish Type II initiators.

The initiator concentration in the solvent can range from about 0.1% toabout 6% w/w. In some embodiments, initiator concentration in thesolvent can be about 0.5% w/w.

The top coat solution may also contain a surfactant. In general, anysurfactant may be used. In some embodiments, surfactants can includesodium lauryl sulfate, Tween 20, Span 80, Triton X-100, Pluronic F68,Pluronic L-81, combinations thereof, and derivatives thereof. Theoptional surfactant can be dissolved into the selected solvent at aconcentration ranging from about 0.1% w/w to about 5% w/w. In someembodiments, the surfactant concentration is about 0.6% w/w.

In some embodiments, to apply the top coat to a base coated catheter,the length of the catheter desired to be coated is inserted into the topcoat solution. The dip time, or amount of time the catheter spends inthe top coat solution, ranges from about 0.2 to about 20 minutes, about0.5 to about 20 minutes, about 2 to about 15 minutes, about 3 to about15 minutes, or about 8 to about 12 minutes. In some embodiments, the diptime can be about 10 minutes.

In some embodiments, the dip time, or amount of time the catheter spendsin the top coat solution, ranges from about 0.2 seconds to about 20minutes, about 0.5 seconds to about 20 minutes, about 2 seconds to about15 minutes, about 3 seconds to about 15 minutes, or about 8 seconds toabout 12 minutes.

In some embodiments, the dip time, or amount of time the catheter spendsin the top coat solution, ranges from about 0.2 seconds to about 20seconds, about 0.5 seconds to about 20 seconds, about 2 seconds to about15 seconds, about 3 seconds to about 15 seconds, or about 8 seconds toabout 12 seconds. In some embodiments, the dip time can be about 5seconds.

In other embodiments, the top coat can be applied by spraying, brushing,spin coating, or the like, or a combination thereof including or notincluding dip coating.

In some embodiments, only portions of the catheter are coated with thetop coat. Therein portions of the catheter can be masked so that topcoat is not applied to the surface under the masked regions.

After dip coating or otherwise applying the top coat, the catheter isexposed to ultraviolet radiation with a wavelength ranging from about 10nm to about 400 nm, about 100 nm to about 400 nm, about 200 nm to about400 nm, about 200 nm to about 300 nm, or about 300 nm to about 400 nm.Combinations of wavelengths in this range can also provide a suitablebase coat. In one embodiment, ultraviolet radiation can be applied by afirst wavelength between about 200 nm to about 300 nm and a secondwavelength between about 300 nm to about 400 nm. In one embodiment,wavelengths can include 254 and 365 nm.

The top coat cure time, or amount of time the catheter is exposed toultraviolet radiation, ranges from about 0.5 to about 4 minutes, about 1to about 4 minutes, about 1 to about 3 minutes, about 0.5 to about 3minutes, about 1 to about 5 minutes, about 0.5 to about 3 minutes, orabout 0.5 to about 50 minutes. In one embodiment, the cure time is about2 minutes.

In some embodiments, the top coat cure time, or amount of time thecatheter is exposed to ultraviolet radiation, ranges from about 0.5 toabout 10 minutes, about 1 to about 10 minutes, about 1 to about 8minutes, about 0.5 to about 8 minutes, about 1 to about 8 minutes, about0.5 to about 8 minutes, or about 0.5 to about 50 minutes. In oneembodiment, the cure time is about 5 minutes.

The herein described coatings can provide a reduction in maximum dynamicfriction force [gf] when compared to an uncoated device. In someembodiments, the coatings can reduce the maximum dynamic friction forceby about 50% or more. In other embodiments, the coatings can reduce themaximum dynamic friction force by about 75% or more. In otherembodiments, the coatings can reduce the maximum dynamic friction forceby about 95% or more. In other embodiments, the coatings can reduce themaximum dynamic friction force by about 75% to about 99%, e.g., about80%-99%, about 85%-99%, about 90%-99%, about 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99%.

The herein described coatings can provide a reduction in average dynamicfriction force at 60 mm displacement for 100 cycles [gf] when comparedto an uncoated device. In some embodiments, the coatings can reduce themaximum dynamic friction force by about 50%. In other embodiments, thecoatings can reduce the maximum dynamic friction force by about 75%. Inother embodiments, the coatings can reduce the maximum dynamic frictionforce by about 95% or more. In other embodiments, the coatings canreduce the maximum dynamic friction force by about 75% to about 99%,e.g., about 80%-99%, about 85%-99%, about 90%-99%, about 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%.

The herein described coatings can provide an increase in lubricity whencompared to an uncoated device. In some embodiments, the coatings canincrease the lubricity by about 50%. In other embodiments, the coatingscan increase the lubricity by about 75%. In other embodiments, thecoatings can increase the lubricity by about 95% or more. In otherembodiments, the coatings can increase the lubricity by about 75% toabout 99%, e.g., about 80%-99%, about 85%-99%, about 90%-99%, about 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

Example 1 Preparation of a Base Coat Polymer

To a 1 L round bottom flask are added 80.0 g of tetrahydrofurfurylacrylate, 18.5 g of 4-hydroxybuyl acrylate and 250 mL of toluene. Thesolution is de-gassed by purging argon gas through for 30 min. Then, 1.0gram AIBN initiator is added, and the mixture is purged with argon foranother 10 min. The flask is immersed in an 80° C. oil bath and refluxcondenser with argon inlet attached. The mixture is heated for 16 hoursunder argon. The reaction is cooled down and precipitated with 1.2 L ofcold MTBE, precipitated product—viscous polymer is collected and driedat vacuum. Typical yield is 85-95%.

The dried polymer is dissolved in dry DMF (200 mL, about 0.5 g/mL) andtreated with 0.84 mL of triethylamine and 3.0 mL of isocyanatoethylacrylate. The mixture is stirred at ambient conditions for 16 hrs. Thepolymer is precipitated out with 0.8 L of water. The polymer isredissolved in 0.2 L acetone and precipitated in 0.8 L water, washed2×300 mL of water and dried at high vacuum.

Example 2 Preparation of a Liquid Base Coat Solution

In an appropriate container, 300 g of polymer from example 1 isdissolved in 2,000 mL of propylene glycol monomethyl ether acetate. Then15 g of Pluronic L-81, 6 g 1-hydroxycyclohexyl phenyl ketone, and 6 gbenzophenone are added. Complete dissolution is achieved with shakingfor 30 minutes producing a clear, homogeneous solution.

Example 3 Preparation of a Top Coat Macromer

Fifty (50) grams of PEG (Mw 4,000) is dried by azeotropic distillationwith toluene. A solution of PEG in 250 mL of toluene is treated with 30mL of dichloromethane, followed by addition of 7.0 mL of triethylamineand 4.04 mL of acryloyl chloride. The reaction mixture is stirred for 5hrs and then precipitated salts are filtered off and top coat macromeris isolated by precipitation from 1 L of cold MTBE. Solids are separatedby filtration, washed with additional 200 mL of MTBE and dried at highvacuum overnight.

Example 4 Preparation of a Top Coat Macromer

Fifty (50) grams of 8-Arm PEG (Mw 20,000) is dried by azeotropicdistillation with toluene. A solution of PEG in 250 mL of toluene istreated with 30 mL of dichloromethane, followed by addition of 0.46 mLof triethylamine and 0.25 mL of acryloyl chloride. The reaction mixtureis stirred for 16 hrs and then precipitated salts are filtered off andtop coat macromer is isolated by precipitation from 1.2 L of cold MTBE.Solids are separated by filtration, washed with additional 200 mL ofMTBE and dried at high vacuum overnight.

Example 5 Preparation of a Top Coat Solution

In a container, 9.0 g of polyethylene glycol di-acrylate (4,000 Mw)prepared in Example 3 is dissolved in 45.0 mL of methanol with shaking.Then, 0.23 g of Pluronic L-81 surfactant, 90 mg of benzophenone, and 90mg of 1-hydroxycyclohexyl phenyl ketone are added. Complete dissolutionwith heating at 55° C. for 2 minutes results in a clear, homogenoussolution.

Example 6 Preparation of a Top Coat Solution

In a container, 400 g of polyethylene glycol acrylate (20 k Mw) preparedin example 4 is dissolved in 2,000 mL of methanol with shaking. Then, 10g of Tween 80 surfactant, 4 g of benzophenone, and 4 g of1-hydroxycyclohexyl phenyl ketone are added. Complete dissolution isachieved with shaking for 30 minutes producing a clear, homogeneoussolution.

Example 7 Coating a Microcatheter

A Harland PCX 175 Coating machine is charged with the basecoat and topcoat solutions prepared in [0066] and [0069] respectively. A catheterwith lengths of outer surface comprised of Grilamid L25 and Pebax35D-72D durometer is prepared for coating by first wiping the outersurface with acetone. The catheter is then plasma treated with argonplasma (365 sccm, 300 watts, 500 mtorr) followed by oxygen plasma (120sccm, 150 watts, 400 mtorr). The catheter is then affixed in the coatingmachine and coated using an automated, pre-programmed recipe. Thesequential stepwise process dips the catheter in basecoat solution,extracts it at 5 cm/sec, UV cures the basecoat for 30 sec (365 nm λ,mJ/cm2 83.7 UV dose), dips the catheter in topcoat solution, extracts itat 0.6 cm/sec, and finally cures the top coat for 300 sec (365 nm λ,837.0 mJ UV dose).

Example 8 Lubricity

Microcatheter samples prepared in Example 7 are tested to evaluatelubricity using an Instron 5943 material tester equipped with a 5 Nstatic load cell. A mechanical clamping fixture is attached to the loadcell to hold the top of the microcatheter sample as its length is pulledthrough a hydraulic clamping fixture (clamping force of 1 lb.) submergedin a heated (37° C.) water bath containing distilled water. The testmethod cycles each sample repeatedly 20 times at a pull rate of 254mm/min for 100 mm, with one cycle measured as starting at 0 mmdisplacement with the hydraulic clamp closed on the sample. Then, thesample is pulled through the hydraulic clamp for 100 mm displacement,and finally the hydraulic clamp is opened, and the sample is returned to0 mm displacement. The maximum dynamic friction force and the averagedynamic friction force at the 60 mm displacement mark is measured andpresented in Table 1 below. Included in the table are lubricitymeasurement results for an uncoated sample run for 20 cycles as acomparison.

TABLE 1 Sample Maximum Dynamic Avg. Dynamic Friction Force NumberFriction Force [gf] at 60 mm Displacement [gf] 1 32.0 27.9 2 32.0 29.0Uncoated 411 305

The coating of example 8 compared to an uncoated sample illustrates anincrease in lubricity.

Although preferred embodiments have been described in this specificationand the accompanying drawings, it will be appreciated that a number ofvariations and modifications may suggest themselves to those skilled inthe pertinent arts. Thus, the scope of the present invention is notlimited to the specific embodiments and examples described herein, butshould be deemed to encompass alternative embodiments and equivalents.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A coating comprising: a base coat including a copolymer of a first tetrahydrofurfuryl monomer and a second monomer, and a top coat including a polyethylene glycol macromer.
 2. The coating of claim 1, wherein the copolymer has a molecular weight between about 15,000 g/mole and about 150,000 g/mole.
 3. The coating of claim 1, wherein the top coat is atop the base coat.
 4. The coating of claim 1, wherein the polyethylene glycol macromer is an 8 arm polyethylene glycol.
 5. The coating of claim 1, wherein the polyethylene glycol macromer has a molecular weight of 20 k g/mole.
 6. A catheter or microcatheter coated with the coating of claim
 1. 7. A coating comprising: a base coat including a first copolymer of a first monomer and a second monomer wherein the first monomer is a tetrahydrofurfuryl monomer, and a top coat including a second copolymer of a third monomer and a fourth monomer wherein the third monomer is an acrylate monomer.
 8. The coating of claim 7, wherein the acrylate monomer is 4-hydroxybutyl acrylate.
 9. The coating of claim 7, wherein the first copolymer has a molecular weight between about 15,000 g/mole and about 150,000 g/mole.
 10. The coating of claim 7, wherein the top coat is atop the base coat.
 11. A catheter or microcatheter coated with the coating of claim
 7. 12. A method of coating a thermoplastic surface, the method comprising: applying a base coat including a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer to the thermoplastic surface, and applying a top coat to the base coat, wherein the top coat includes a hydrophilic polymer.
 13. The method of claim 12, wherein the thermoplastic surface is plasma treated before applying the base coat.
 14. The method of claim 12, wherein the base coat, the top coat, or both is applied by dipping.
 15. The method of claim 12, wherein the base coat is exposed to ultraviolet radiation.
 16. The method of claim 15, wherein the ultraviolet radiation is at a wavelength ranging from about 10 nm to about 400 nm.
 17. The method of claim 16, wherein the base coat cures for about 0.5 to about 10 minutes.
 18. The method of claim 12, wherein the top coat is exposed to ultraviolet radiation.
 19. The method of claim 15, wherein the ultraviolet radiation is at a wavelength ranging from about 10 nm to about 400 nm.
 20. The method of claim 16, wherein the top coat cures for about 0.5 to about 10 minutes. 